Kommersiellt obunden läkemedelsinformation riktad till läkare och sjukvårdspersonal

Dolutegravir

Klassificering: C

Preparat: DOVATO, Juluca, Tivicay, TIVICAY, Triumeq

ATC kod: J05AR, J05AR13, J05AR21, J05AR25, J05AX12

Substanser: dolutegravir, dolutegravirnatrium

Sammanfattning

Det saknas kontrollerade studier om skillnader mellan könen avseende effekt av dolutegravir. En populationskinetisk studie baserad på data poolade från flera studier kunde inte se kliniskt relevanta skillnader mellan könen avseende exponeringen för dolutegravir. Observationella studier har visat att kvinnor oftare än män avbröt behandling med dolutegravir till följd av biverkningar.

Preliminära resultat har visat ökad risk för neuralrörsdefekt hos barn som exponerats för dolutegravir under fostertiden. Användning av dolutegravir hos flickor/kvinnor som kan tänkas bli gravida bör därför undvikas. För mer information, se kunskapsstödet Janusmed fosterpåverkan.

Additional information

Pharmacokinetics and dosing

A population pharmacokinetic study based on data from 563 individuals (481 men, 82 women), identified factors that contribute to variability in dolutegravir pharmacokinetics. These factors were then used in a model to explore the pharmacokinetic/pharmacodynamic relationship [1]. In the final model, sex was a predictor of bioavailability. Oral bioavailability was 21% (95% CI 13-29%) higher in women than in men [1]. In a simulation based on the model, dolutegravir Cmax, AUC and Cmin were 32%, 26% and 15% higher in women, respectively, but these differences are not considered clinically significant and therefore no dose adjustment will be  necessary [1]. Population pharmacokinetic analyses using pooled data from Phase IIb and Phase III adult trials have not shown any clinically relevant sex difference in dolutegravir exposure [2].

Effects

Both men and women have been included in the pivotal studies, although the majority of subjects included have been men (70%-85%) [3, 4]. Data on effect of dolutegravir has not been presented by sex in these studies.

Adverse effects

In a study of adverse effects (AE) of integrase inhibitor-based therapies (in total 1704 patients, of whom 909 men and 70 women were treated with dolutegravir), discontinuation of dolutegravir due to an AE was seen in 6.3% and 15.7% of men and women, respectively [5]. Neuropsychiatric AE leading to discontinuation was reported in 4.6% in men and 10% in women. Relative hazards (RHs) for discontinuation of dolutegravir both due to any AE or neuropsychiatric AEs were higher in women, with a RH of 2.81 (p=0.002) for any AW and a RH of 2.64 (p=0.01) for neuropsychiatric AEs [5].

Another study assessed factors for discontinuing integrase inhibitor therapy in the Swiss HIV Cohort Study. The study population included 4,041 individuals, of whom 1455 men and 495 women were treated with dolutegravir. The only independent risk factor for modifying HIV treatment due to toxicity was female sex (HR 1.98, p<0.001) [6].

Reproductive health issues

Preliminary results from a study of almost 12,000 children born to women with HIV showed a higher risk of neural tube defects among children whose mothers who on dolutegravir-based ART when they became pregnant compared to mothers on other ART (0.9% vs. 0.1%). Until further information is available, EMA advices against dolutegravir treatment in women who are seeking to become pregnant and recommends that women of childbearing age on dolutegravir treatment should use effective contraception [7,8]. Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Other information

According to the product information, dolutegravir had no pharmacodynamic effect on luteinizing hormone, follicle stimulating hormone, or progesterone. No dose adjustment of oral contraceptives or dolutegravir is necessary in co-administration [2].

Försäljning på recept

Fler män än kvinnor hämtade ut läkemedel innehållande dolutegravir (ATC-kod J05AX12) på recept i Sverige år 2016, totalt 510 män och 305 kvinnor. Den fasta kombinationen av dolutegravir med lamivudin och abakavir (ATC-kod J05AR13) ut av 1054 män och 705 kvinnor  [9].  Samtidigt är ca 2/3 av personer som lever med hiv i Sverige i dag män [10].

Uppdaterat: 2018-08-13

Litteratursökningsdatum: 2017-07-14

Referenser

  1. Zhang J, Hayes S, Sadler BM, Minto I, Brandt J, Piscitelli S et al. Population pharmacokinetics of dolutegravir in HIV-infected treatment-naive patients. Br J Clin Pharmacol. 2015;80:502-14. PubMed
  2. Tivicay (dolutegravir). EPAR - Product information. European Medicines Agency (EMA); 2017.
  3. Raffi F, Rachlis A, Stellbrink HJ, Hardy WD, Torti C, Orkin C et al. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study. Lancet. 2013;381:735-43. PubMed
  4. Cahn P, Pozniak AL, Mingrone H, Shuldyakov A, Brites C, Andrade-Villanueva JF et al. Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study. Lancet. 2013;382:700-8. PubMed
  5. Hoffmann C, Welz T, Sabranski M, Kolb M, Wolf E, Stellbrink HJ et al. Higher rates of neuropsychiatric adverse events leading to dolutegravir discontinuation in women and older patients. HIV Med. 2017;18:56-63. PubMed
  6. Elzi L, Erb S, Furrer H, Cavassini M, Calmy A, Vernazza P et al. Adverse events of raltegravir and dolutegravir. AIDS. 2017;31:1853-1858. PubMed
  7. New study suggests risk of birth defects in babies born to women on HIV medicine dolutegravir. European Medicines Agency (EMA) [www]. [cited 2018-08-13]. länk
  8. Dolutegravir ska inte användas av kvinnor som önskar bli gravida. Läkemedelsverket [www]. [cited 2018-08-13]. länk
  9. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2016 [cited 2017-05-20.] länk
  10. Hivinfektion 2016. Folkhälsomyndigheten (The Public Health Agency of Sweden): Stockholm, Sweden.

Författare: Jaran Eriksen

Faktagranskat av: Mia von Euler

Godkänt av: Karin Schenck-Gustafsson